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The antiinflammatory endothelial tyrosine kinase Tie2 interacts with a novel nuclear factor-kB inhibitor ABIN-2

By David P. Hughes, Marie B. Marron and Nicholas P.J. Brindle


Tie2 is a receptor tyrosine kinase expressed predominantly in endothelial cells and is essential for blood vessel formation and maintenance. The receptor has potent antiinflammatory effects on endothelial cells, suppressing vascular endothelial growth factor– and tumor necrosis factor–induced expression of leukocyte adhesion molecules and procoagulant tissue factor and inhibiting vascular leakage. To delineate the signaling pathways utilized by Tie2, we performed yeast two-hybrid screening of a human endothelial cell cDNA library and identified a novel protein interacting with the intracellular domain of the receptor. This protein was found to be human A20 binding inhibitor of NF-κB activation-2, ABIN-2, an inhibitor of NF-κB–mediated inflammatory gene expression. Coexpression of Tie2 and ABIN-2 in CHO cells confirmed the interaction occurs in mammalian cells. In contrast, Tie1 did not interact with ABIN-2 in the yeast two-hybrid system or mammalian cells. Deletion analysis identified the Tie2 binding motif to be encompassed between residues 171 and 272 in ABIN-2. Interaction was dependent on Tie2 autophosphorylation but ABIN-2 was not tyrosine phosphorylated by Tie2. Furthermore, in endothelial cells the interaction was stimulated by the Tie2 ligand angiopoietin-1. Expression of ABIN-2 deletion mutants in endothelial cells suppressed the ability of angiopoietin-1 to inhibit phorbol ester–stimulated NF-κB–dependent reporter gene activity. These findings provide the first direct link between Tie2 and a key regulator of inflammatory responses in endothelial cells. Interaction between Tie2 and ABIN-2 may be important in the vascular protective antiinflammatory actions of Tie2.Peer-reviewedPublisher Versio

Publisher: American Heart Association, Inc.
Year: 2003
DOI identifier: 10.1161/01.RES.0000063422.38690.DC
OAI identifier:

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  1. (1999). 4: diverging gene counterparts in mice and humans. doi
  2. (1996). A20 blocks endothelial cell activation through a NF-B–dependent mechanism. doi
  3. (2000). Angiopoietin-1 induces endothelial cell sprouting through the activation of focal adhesion kinase and plasmin secretion. Circ Res. doi
  4. (1998). Angiopoietin-1 induces sprouting angiogenesis in vitro. Curr Biol. doi
  5. Angiopoietin-1 inhibits endothelial cell apoptosis via the Akt/Survivin pathway.
  6. Angiopoietin-1 inhibits irradiation- and mannitol-induced apoptosis in endothelial cells. doi
  7. (2000). Angiopoietin-1 is an antipermeability and antiinflammatory agent in vitro and targets cell junctions. Circ Res. doi
  8. Angiopoietin-1 negatively regulates expression and activity of tissue factor in endothelial cells.
  9. (2000). Angiopoietin-1 protects the adult vasculature against plasma leakage. Nat Med. doi
  10. Angiopoietin-1 reduces VEGF-stimulated leukocyte adhesion to endothelial cells by reducing ICAM-1, VCAM-1, and E-Selectin expression. Circ Res. doi
  11. Angiopoietin-1 regulates endothelial cell survival through the phosphatidylinositol 3-kinase/Akt signal transduction pathway. doi
  12. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis.
  13. Chemotactic properties of angiopoietin-1 and -2, ligands for the endothelial-specific receptor tyrosine kinase Tie2. doi
  14. Direct actions of angiopoietin-1 on human endothelium: evidence for network stabilization, cell survival, and interaction with other angiogenic growth factors. Lab Invest.
  15. Dok-R plays a pivotal role in angiopoietin-1– dependent cell migration through recruitment and activation of Pak. doi
  16. (1994). Dominant-negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo. Genes Dev. doi
  17. (1985). Enhanced chemiluminescent method for the detection of DNA dot-hybridization assays. Anal Biochem. doi
  18. Evidence for heterotypic interaction between the receptor tyrosine kinases TIE-1 and TIE-2. doi
  19. Failure to regulate TNF-induced NF-B and cell death responses in A20-deficient mice.
  20. Functional redundancy of the zinc fingers of A20 for inhibition of NF-B activation and protein-protein interactions. doi
  21. (1996). Genomic libraries and a host strain designed for highly efficient two-hybrid selection in yeast.
  22. GRB2 and SH-PTP2:potentially important endothelial signaling molecules downstream of the TEK/TIE2 receptor tyrosine kinase.
  23. Identification of a novel A20-binding inhibitor of nuclear factor-B activation termed ABIN-2. doi
  24. (1999). Identification of Tek/Tie2 binding partners: binding to a multifunctional docking site mediates cell survival and migration. doi
  25. (1996). Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. doi
  26. (1999). Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. doi
  27. (1995). Predicting coiled coils by use of pairwise residue correlations. doi
  28. (1999). Role of PI 3-kinase in angiopoietin-1–mediated migration and attachment-dependent survival of endothelial cells. Exp Cell Res. doi
  29. The Shc-related adaptor protein, Sck, forms a complex with the vascular-endothelial-growth-factor receptor KDR in transfected cells. doi
  30. (1998). The Tek/Tie2 receptor signals through a novel Dok-related docking protein, doi
  31. (2003). The zinc finger protein A20 inhibits TNF-induced NF-B-dependent gene expression by interfering with an RIP- or TRAF2-mediated transactivation signal and directly binds to a novel NF-B–inhibiting protein ABIN. doi
  32. (2001). Tie receptors: new modulators of angiogenic and lymphangiogenic responses. Nat Rev Mol Cell Biol.
  33. (1992). Transcriptional activation of the tumor necrosis factor-–inducible zinc finger protein, A20, is mediated by B elements.
  34. Tumor necrosis factor- induction of novel gene products in human endothelial cells including a macrophage-specific chemotaxin.
  35. (1998). Tyrosine 1101 of Tie2 is the major site of association of p85 and is required for activation of phosphatidylinositol 3-kinase and Akt. Mol Cell Biol. doi
  36. (1999). Vessel cooption, regression, and growth in tumors mediated by angiopoietins

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